Multiple Sclerosis: A Theory
James Howard
This is a new theory of the cause of multiple sclerosis (MS).
My explanation is based on my theory of the interaction of
the hormones, melatonin (MLT) and dehydroepiandrosterone
(DHEA), which I call the "melatonin - DHEA cycle," and
testosterone, and the effects these have on the nervous and
immune systems. I suggest all tissues are dependent on the
MLT - DHEA cycle, principally the nervous and immune
systems, and the gonadal (sexual) hormones evolved as a
means of manipulating this cycle. MS is a disease
characterized by demyelination of nerves. At its most basic,
my work suggests MS results from an "attack" of the
immune system on myelin, as a result of over-stimulation of
the MLT - DHEA cycle in the immune system, triggered by
lack of normal growth of myelin, as a result of deficient
effects of testosterone. (The following treatise explains this
in detail, it will take some length to do this. Please bear with
me. Since this is written for internet posting, I am not
including diagrams here; they may be accessed in the articles
I specify on the internet.)
In 1985, I developed a theory of sleep that explains the
connection of MLT with DHEA. (This may be read in detail
at http://www.naples.net/~nfn03605 on the internet.) The
importance of my sleep mechanism to MS is that it explains
that when MLT levels are high, DHEA is low, and when
DHEA is high, MLT levels are low. My work further says
that DHEA levels will rebound to the suppression of DHEA
caused by MLT. It is a "cycle." A direct connection of
MLT and MS has been reported by two investigators,
Sandyk and Awerbuch. Since no work has been done on
MS and DHEA, I will show how their work to supports the
connection of the MLT - DHEA cycle to MS. MS cannot be
explained by melatonin alone.
In an abstract of International Journal of Neuroscience 1993;
68: 209, Sandyk explains the connection of MLT and MS:
"Epidemiological studies demonstrate that the incidence of
multiple sclerosis (MS) is age-dependent being rare prior to
age 10, unusual prior to age 15, with a peak in the mid 20s.
It has been suggested that the manifestation of MS is
dependent upon having passed through the pubertal period.
In the present communication, I propose that critical changes
in pineal melatonin secretion, which occur in temporal
relationship to the onset of puberty, are intimately related to
the timing of onset of the clinical manifestations of MS.
Specifically, it is suggested that the fall in melatonin
secretion during the prepubertal period, which may disrupt
pineal-mediated immunomodulation, may stimulate either the
reactivation of the infective agent or increase the
susceptibility to infection during the pubertal period.
Similarly, the rapid fall in melatonin secretion just prior to
delivery may account for the frequent occurrence of relapse
in MS patients during the postpartum period. In contrast,
pregnancy, which is associated with high melatonin
concentrations, is often accompanied by remission of
symptoms. Thus, the presence of high melatonin levels may
provide a protective effect, while a decline in melatonin
secretion may increase the risk for the development and
exacerbation of the disease. The melatonin hypothesis of
MS may explain other epidemiological and clinical
phenomena associated with the disease such as the low
incidence of MS in black African and American populations,
..."
Melatonin is produced in the pineal gland. It is known that
calcification of the pineal gland occurs with age and the
reduction of MLT. Sandyk and Awerbuch address this in
MS.
"Twenty-one age and sex-matched neurological patients
served as controls. PC [pineal calcification] was seen in
100% of MS patients, while 72.4% patients had CPC
[choroid plexus calcification]. In the control sample, PC was
found in 42.8% and CPC in 28.5%. Thus, the strikingly high
prevalence between MS and abnormalities of the pineal
gland. Moreover, since pineal melatonin is involved in
neuroimmunomodulation, we propose, for the first time, that
abnormalities of pineal melatonin functions are implicated in
the pathophysiology of the disease [MS]." (International
Journal of Neuroscience 1991; 61: 61) Melatonin is
produced in the highest levels during nighttime, lowest in
daytime. In a study of nocturnal melatonin levels, Sandyk
and Awebuch, reported that: "Abnormal melatonin levels
were found in 13 patients (52.0%), 11 of whom had
nocturnal levels which were below the daytime values."
(International Journal of Neuroscience 1992; 67: 173)
Calcification of the pineal increases with age. Now, this fits
my theory. If MS represents a state in which the MLT -
DHEA cycle is increased, then the MLT - DHEA cycle will
increase. This will literally increase aging, part of which
would show as increased calcification of the pineal gland.
I suggest it is the connection of MLT with DHEA that is the
real connection of MLT with MS. In Sandyks summary
(1993), he describes the age-dependence of MS. These ages
are very important to my explanation of MS, but I want to
postpone them momentarily and directly consider the times
and levels of melatonin he lists. My work at my internet
page explains why, and shows actual measurements, of MLT
and DHEA during the human life-span. When MLT starts its
steep decline just prior to puberty, DHEA starts a strong
increase, known as "adrenarche." My work suggests this
rise occurs, because the brain is finishing its use of DHEA
for growth and development in infants and children. What is
really happening is that the "measurable" levels of DHEA
are rapidly increasing as less and less DHEA is absorbed by
the brain for growth and development. The importance of
this rise in DHEA for MS is that this "free" DHEA can then
be used by the immune system. (My work suggests all
tissues compete for DHEA; the brain is simply the best at
absorbing it. I will explain how DHEA affects the immune
system below.) Sandyk suggests that "the fall in melatonin
secretion during the prepubertal period, which may disrupt
pineal-mediated immunomodulation, may stimulate either the
reactivation of the infective agent or increase the
susceptibility to infection during the pubertal period." (A
number of citations suggest that an infective agent is
involved in MS; this is why he mentions an infective agent.
My explanation suggests these potential infections merely
stimulate increased DHEA; they are not the actual cause of
MS. This will be explained.) Further, Sandyk says:
"Similarly, the rapid fall in melatonin secretion just prior to
delivery may account for the frequent occurrence of relapse
in MS patients during the postpartum period. In contrast,
pregnancy, which is associated with high melatonin
concentrations, is often accompanied by remission of
symptoms." The protective effect Sandyk suggests for
melatonin here is, I suggest, simply due to another use of
DHEA, similar to that of the brain in infants and children,
which I described above. My work suggests that tissues use
DHEA, therefore, the mother makes DHEA for herself and
her fetus. This stimulates the MLT - DHEA cycle in the
mother; her melatonin increases to stimulate DHEA in large
amounts for the growing fetus. This DHEA is absorbed by
the rapid growth of the fetus, so the DHEA levels actually
stay low in the pregnant woman. Her immune system is not
activated enough to start the MS cycle. Since DHEA may be
involved in starting delivery: "labor is associated with a
significant increase in umbilical artery levels of DHEA"
(Journal of Clinical Endocrinology and Metabolism 1976;
42: 744), available DHEA rises at birth. That is, the fetus
stops using DHEA, which then becomes available to
stimulate tissues in the mother. It is this rise in DHEA at
birth that starts contractions and also stimulates the immune
system, and increases MS. So, I am saying that the
"protective" effects of high melatonin result from the fact
that melatonin is high when a very large amount of DHEA is
needed for growth and development. These two times of
high melatonin are times of high DHEA and high DHEA use;
melatonin does not protect against MS. The connection of
MLT is DHEA.
My work suggests that DHEA directly stimulates the immune
system. This can be seen quite well in a number of studies of
HIV infection and AIDS. (Please read my article on
"AIDS" at my website for citations.) What is found is that
DHEA increases dramatically upon infection by the HIV. I
think DHEA increases whenever infection, bacterial or viral,
occurs. MS appears to be associated with viruses; the
hypothesis depends on the findings that MS often appears in
a cluster.
"Geographic and temporal variation and migration studies
point to an exogenous agent in the etiology of multiple
sclerosis. If infectious etiology is involved, space-time
clustering would also be expected. The authors analyzed 381
patients with a clinical onset of multiple sclerosis between
1953 and 1987 in the county of Hordaland, Norway. Patients
[MS] within the same birth cohort had lived significantly
closer to each other than would be expected during ages 13-
20 years, with peak clustering at age 18 years (p = 0.002).
Clustering was also shown between patients in pairs
comprised of one individual with initial remittent disease and
the other with chronic progressive course of disease,
suggesting a similar etiology for both clinical patterns.
Clustering between cases with widely divergent dates of
clinical onset provides evidence of marked variation in
latency. No similar clustering was observed in age-, sex-, and
area-matched hospital controls without multiple sclerosis,
and no clustering was found among the cases when using
fixed number of years before onset. These results are
compatible with a common infectious agent, such as the
Epstein-Barr virus, acquired in adolescence in genetically
vulnerable persons who are also not protected by an
infection acquired before this age of susceptibility."
(American Journal of Epidemiology 1991; 133: 932)
There are other studies that suggest viral infections may be
part of the mechanism of MS. However, I suggest that viral
infections are merely activating the MLT - DHEA cycle. The
increased DHEA activates "monitoring" by the immune
system. The increased monitoring of the immune system
picks up a "lesion" that causes an "autoimmune response"
that causes the MS. Now, I suggest that this mechanism,
which will be described below, can manifest itself without
the influence of an infection. An infection simply increases
the probability; infections are not the actual cause of MS.
DHEA and cortisol are the major hormones produced by the
adrenal glands. DHEA and cortisol secretions may be
separated, but often these occur simultaneously. While no
one has measured DHEA in MS, and it might actually be
"low" during active MS because of use by the immune
system, two studies have found cortisol to be "significantly
higher" in MS (Experimental and Clinic Endocrinology and
Diabetes 1996; 104: 31; Journal of Clinical Endocrinology
and Metabolism 1994; 79: 848). While this does not prove
that DHEA is involved, it does show that the adrenal glands
are very active in MS.
To summarize to this point, I suggest MS is a state of
activated DHEA production that stimulates the immune
system to attack a "lesion." I suggest the lesion that
provides the "initial antigenic material to the immune
system" results from immature myelin in people with MS.
"In a correlative study involving protein chemical, mass
spectrometric, and electron microscopic techniques we have
determined that myelin obtained from victims of MS is
arrested at the level of the first growth spurt (within the first 6
yr of life) and is therefore developmentally immature. ...We
postulate that this developmentally immature myelin is more
susceptible to degradation by one or a combination of factors
mentioned above, providing the initial antigenic material to
the immune system." (Journal of Clinical Investigation
1994; 94: 146) The "factors" suggested by these
investigators are "genetic, environmental, infective, and
immunological factors..."
What causes the immature myelin in MS that stimulates the
immune system? A number of factors caused me to look at
the connection of testosterone in MS. These include: "A
review of population studies demonstrates that the
preponderance of women in MS is almost a constant."
(Canadian Journal of Neurological Sciences 1992; 19: 466);
"Mortality rates from MS show a well-known north-south
gradient, both within the United States and internationally."
(Neuroendocrinology 1992; 11: 244); "The data suggest
that onset of pathogenesis of MS is dependent on passing or
having passed through the puberty period." (American
Journal of Epidemiology 1981; 114: 24); "MS is rare among
the indigenous black people of Africa." (Journal of
Neurology, Neurosurgery and Psychiatry 1994; 57: 1064).
Testosterone is lower in women. My theory, from which this
work is derived, suggests that the hominids that migrated out
of Africa, into the north, were hominids of lower
testosterone. Therefore, in general, I expect lower
testosterone in Europeans (Whites) than Africans (Blacks.)
European and whites represent lower testosterone. DHEA
increases, starting at adrenarche, to a high point in the mid-
twenties. This fits the findings listed by Sandyk, early in the
paper, that is, that MS peaks in the mid 20s. DHEA would
be highest at this time and, therefore, the immune attack
would be greatest at this time. Earlier this month, I
developed an explanation for migraine headaches that
suggested migraines are caused by increased DHEA. As part
of my support of my explanation of migraines, I pointed out
that blacks produce significantly more testosterone than
whites (Journal of the National Cancer Institute 1986; 76:
45). My work suggested testosterone causes DHEA to be
reduced in the blood, because testosterone causes DHEA to
be used more by "testosterone target tissues;" Blacks have
fewer migraines than whites. This fit very nicely with this
work, too, i.e., MS is rare in blacks. The increased
testosterone in blacks would reduce the immune response of
MS. However, I found out that women MS patients had
"significantly higher concentrations of total and free
testosterone" (Journal of Internal Medicine 1989; 226: 241).
This contradiction caused me to find and propose a reason
for the "lesion" of MS, the immature myelin. I suggest the
immature myelin of MS results from lack of testosterones
effect on growth. I am saying that myelin growth occurs
because of two different hormones. The early large
production of DHEA following birth causes the early growth
of myelin of the "first growth spurt." Subsequent to this, the
nervous system becomes a "testosterone target tissue." That
is, testosterone stimulates growth of the nervous system too.
Men produce more testosterone than women; the brains of
men are bigger than the brains of women. Based on the
following quotation, I am saying that the "white matter" of
the brain is a testosterone target tissue. The "metabolic
activity" of white matter is mainly due to myelin. Myelin is
sensitive to the levels of testosterone.
"Previous results obtained in this laboratory indicate that in
the rat brain the 5 alpha-reductase, the enzymatic activity
involved in metabolizing testosterone into 5 alpha-androstan-
17 beta-ol-3-one (dihydrotestosterone), particularly
concentrated in the white matter. ...The high metabolic
activity associated with the white matter structures appears to
be linked to the presence of myelin, since the specific
activity of the enzyme is particularly elevated in purified
preparations of myelin sheaths." (Journal of Steroid
Biochemistry 1988; 31: 173).
I suggest that the low testosterone of women, and people
whose ancestors developed in the north, is interacting with a
genetic predisposition toward weak, or malfunctioning, 5
alpha-reductase in the nervous system. This could result in
the "immature myelin" found in MS and the significantly
increased testosterone in female MS patients. That is, these
women are not absorbing and converting their testosterone.
Therefore, I suggest multiple sclerosis is the result of
increased DHEA, causing the immune system to attack the
immature myelin. This explains the chronic demyelination
of multiple sclerosis.
James Howard